Title: Tumor-selective mitochondrial network collapse induced by atmospheric gas plasma-activated medium
Abstract: // Kosuke Saito 1, 2 , Tomohiko Asai 3 , Kyoko Fujiwara 1, 2 , Junki Sahara 3 , Haruhisa Koguchi 4 , Noboru Fukuda 5 , Miki Suzuki-Karasaki 6 , Masayoshi Soma 1, 2 , Yoshihiro Suzuki-Karasaki 1, 7 1 Innovative Therapy Research Group, Nihon University Research Institute of Medical Science, Tokyo, Japan 2 Division of General Medicine, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan 3 Department of Physics, College of Science and Technology, Nihon University, Tokyo, Japan 4 The National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan 5 Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan 6 Department of Dermatology, Nihon University Surugadai Hospital, Saitama, Japan 7 Division of Physiology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan Correspondence to: Yoshihiro Suzuki-Karasaki, e-mail: [email protected] Keywords: non-thermal atmospheric gas plasma (AGP), AGP-activated medium, mitochondrial network, reactive oxygen species (ROS), tumor-selective killing Received: November 19, 2015 Accepted: February 09, 2016 Published: March 03, 2016 ABSTRACT Non-thermal atmospheric gas plasma (AGP) exhibits cytotoxicity against malignant cells with minimal cytotoxicity toward normal cells. However, the mechanisms of its tumor-selective cytotoxicity remain unclear. Here we report that AGP-activated medium increases caspase-independent cell death and mitochondrial network collapse in a panel of human cancer cells, but not in non-transformed cells. AGP irradiation stimulated reactive oxygen species (ROS) generation in AGP-activated medium, and in turn the resulting stable ROS, most likely hydrogen peroxide (H 2 O 2 ), activated intracellular ROS generation and mitochondrial ROS (mROS) accumulation. Culture in AGP-activated medium resulted in cell death and excessive mitochondrial fragmentation and clustering, and these responses were inhibited by ROS scavengers. AGP-activated medium also increased dynamin-related protein 1-dependent mitochondrial fission in a tumor-specific manner, and H 2 O 2 administration showed similar effects. Moreover, the vulnerability of tumor cells to mitochondrial network collapse appeared to result from their higher sensitivity to mROS accumulation induced by AGP-activated medium or H 2 O 2 . The present findings expand our previous observations on death receptor-mediated tumor-selective cell killing and reinforce the importance of mitochondrial network remodeling as a powerful target for tumor-selective cancer treatment.